REVIEW ARTICLE
Indole as an intercellular signal in microbial communities First published online with the title ‘Intercellular signal indole in microbial communities’ on 7 January 2010.
Jin-Hyung Lee & Jintae Lee School of Display & Chemical Engineering, Yeungnam University, Gyeongsan, Korea
Correspondence: Jintae Lee, School of Display & Chemical Engineering, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Korea. Tel.: 182 53 810 2533; fax: 182 53 810 4631; e-mail:
[email protected] Received 16 August 2009; revised 1 December 2009; accepted 6 December 2009. Final version published online 7 January 2010. DOI:10.1111/j.1574-6976.2009.00204.x Editor: Miguel Camara
MICROBIOLOGY REVIEWS
Keywords indole; signal molecule; autoinducer 2; biofilm; signal interference.
Abstract Bacteria can utilize signal molecules to coordinate their behavior to survive in dynamic multispecies communities. Indole is widespread in the natural environment, as a variety of both Gram-positive and Gram-negative bacteria (to date, 85 species) produce large quantities of indole. Although it has been known for over 100 years that many bacteria produce indole, the real biological roles of this molecule are only now beginning to be unveiled. As an intercellular signal molecule, indole controls diverse aspects of bacterial physiology, such as spore formation, plasmid stability, drug resistance, biofilm formation, and virulence in indole-producing bacteria. In contrast, many non-indole-producing bacteria, plants and animals produce diverse oxygenases which may interfere with indole signaling. It appears indole plays an important role in bacterial physiology, ecological balance, and possibly human health. Here we discuss our current knowledge and perspectives on indole signaling.
Introduction In most environmental niches, multiple bacterial species coexist as dynamic communities. Bacteria have developed intercellular signaling to adapt and survive in natural communities because of nutritional limitation, competition with other bacteria, and the host defense system. Many bacteria secrete small diffusible signal molecules to sense the local environmental conditions, including their own population, and to synchronize multicellular behaviors (Fuqua et al., 1994; Waters & Bassler, 2005; Keller & Surette, 2006; Hughes & Sperandio, 2008). A variety of intercellular signal molecules, such as the most studied N-acyl-homoserine lactones (AHLs) in Gram-negative bacteria, autoinducer 2 (AI-2) in both Gram-negative and Gram-positive bacteria, and signal peptides in Gram-positive bacteria, among others, have been discovered over the last 20 years (Waters & Bassler, 2005; Keller & Surette, 2006; Dong et al., 2007). The intercellular signal molecules coordinate the gene expression for bioluminescence, sporulation, plasmid conjugal transfer, competence, virulence factor production, antibiotic production, and biofilm formation (Fuqua et al., 1994; Comella & Grossman, 2005; Waters & Bassler, 2005; Nadell et al., 2008). There has been widespread research on new signal molecules and their signaling mechanisms in this 2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
area, and canonical signaling systems of AHL quorum sensing have been extensively reviewed elsewhere (Waters & Bassler, 2005; Keller & Surette, 2006; Dong et al., 2007; Williams et al., 2007). Recently, the concept of intercellular signaling has been broadened, and is no longer restricted to cell–cell communication such as quorum sensing (Monds & O’Toole, 2008; Ryan & Dow, 2008) or limited to intraspecies signaling, but now includes interspecies and interkingdom signaling (Bassler, 1999; Shiner et al., 2005; Diggle et al., 2007a; Hughes & Sperandio, 2008; Ryan & Dow, 2008). Among the bacterial signal molecules, indole has recently received much attention due to its diverse biological roles in several bacterial strains. This review focused primarily on indole signaling. In 1897, reports showed that Bacillus coli (Escherichia coli) and Asiatic cholera (Vibrio cholerae) produced indole during a stationary cell growth phase (Smith, 1897), and the indole test has been regularly used as a diagnostic marker for the identification of E. coli (Smith, 1897; Wang et al., 2001). Table 1 shows a compilation from the literature of indoleproducing organisms and organisms having homologues of the TnaA tryptophanase (Deeley & Yanofsky, 1981) from E. coli responsible for the biosynthesis of indole. The table demonstrates that a variety of both Gram-positive and Gram-negative bacteria (more than 85 species), including FEMS Microbiol Rev 34 (2010) 426–444
427
Indole signaling in microbial community
Table 1. TnaA encoding and indole-producing bacteria Species Gram-positive bacteria Alkaliphilus metalliredigens Bacillus alvei Bacillus thuringiensis Clostridium novyi Clostridium limosum Clostridium tetani Corynebacterium acnes Desulfotomaculum reducens Desulfitobacterium hafniense Nocardioides sp. Oribacterium sinus Propionibacterium acnes Enterococcus faecalis Symbiobacterium thermophilum Gram-negative bacteria Aeromonas hydrophila Aeromonas liquefaciens Aeromonas punctata Aeromonas salmonicida Bacteroides thetaiotaomicron Bacteroides sp. Brachyspira hyodysenteriae Burkholderia sp. Chromobacterium violaceum Chryseobacterium gleum Citrobacter sp. Citrobacter freundii Citrobacter intermedius Citrobacter koseri Desulfovibrio vulgaris Dichelobacter nodosus Edwardsiella tarda Enterobacter aerogenes Enterobacter liquefaciens Escherichia albertii Escherichia coli Escherichia fergusonii Flavobacteria bacterium Flavobacterium sp. Fusobacterium nucleatum Fusobacterium polymorphum Haemophilus influenzae Haemophilus somnus Haloarcula marismortui Halogeometricum borinquense Hyphomonas neptunium Klebsiella ornithinolytica Klebsiella oxytoca Klebsiella planticola Micrococcus aerogenes Morganella morganii Oxalobacter formigenes Pantoea agglomerans Paracolobactrum coliforme Pasturella multocida Pasturella pneumotropica
FEMS Microbiol Rev 34 (2010) 426–444
Identity with E. coli TnaA (%)
Indole production
References
50 NA 42 54 NA 43–47 NA 54 47 41 31 46 NA 45
ND 1 1 1 1 1 ND 1 1 1 1 1 1
ND Hoch & Demoss (1965) Lecadet et al. (1999) Nishida & Nakagawara (1964) Elsden et al. (1976) Elsden et al. (1976) DeMoss & Moser (1969) ND Christiansen & Ahring (1996) Behrend & Heesche-Wagner (1999) Carlier et al. (2004) Jakab et al. (1996) Schleifer et al. (1984) Ohno et al. (2000)
53 NA NA 52 43 NA 51 40 53 44 NA 42 42 42 54 45 NA 57 NA 99 100 99 44 44 30–45 30 80–90 88 39 42 41 NA NA NA NA NA 34 44–50 NA 88 NA
1 1 1 1/ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1/ 1 1 1 1 1 1
Cumberbatch et al. (1979) DeMoss & Moser (1969) Gilardi (1967) Pavan et al. (2000) Tannock (1977) DeMoss & Moser (1969) Jansson et al. (2004) Laurie & Lloyd-Jones (1999) Riveros et al. (1989) Yamaguchi & Yokoe (2000) Booth & McDonald (1971) Holmes et al. (1974) Sedlak et al. (1971) Holmes et al. (1974) Postgate & Campbell (1966) Dewhirst et al. (1990) Amandi et al. (1982) von Graevenitz (1971) Smith et al. (1971) Huys et al. (2003) Smith (1897) Farmer et al. (1985) Pickett (1989) Pickett (1989) Langworth (1977) Langworth (1977) Kilian (1976) Garcia-Delgado et al. (1977) Nicolaus et al. (1999) Montalvo-Rodriguez et al. (1998) Moore (1981) Liu et al. (1997) Alves et al. (2006) Liu et al. (1997) DeMoss & Moser (1969) O’Hara et al. (2000) Allison et al. (1985) Gavini et al. (1989) DeMoss & Moser (1969) Clemons & Gadberry (1982) Simmons & Simpson (1977)
2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
428
J.-H. Lee & J. Lee
Table 1. Continued. Species
Identity with E. coli TnaA (%)
Indole production
References
Photobacterium harveyi Photorhabdus luminescens Plesiomonas shigelloides Porphyromonas asaccharolytica Porphyromonas endodontalis Porphyromonas gingivalis Prevotella intermedia Proteus inconstans Proteus vulgaris Providencia alcalifaciens Providencia rettgeri Providencia rustigianii Providencia stuartii Pseudovibrio sp. Rhizobium leguminosarum bv. trifolii Saccharomonospora viridis Salinibacter ruber Shewanella sediminis Shigella boydii Shigella dysenteriae Shigella flexneri Shigella sonnei Sphaerophorus varius Spirosoma linguale Stigmatella aurantiaca Treponema denticola Vibrio alginolyticus Vibrio cholerae Vibrio fluvialis Vibrio harveyi Vibrio hollisae Vibrio mediterranei Vibrio nigripulchritudo Vibrio orientalis Vibrio parahaemolyticus Vibrio splendidus Vibrio tapetis Vibrio tubiashii Vibrio vulnificus Yersinia enterocolitica Yersinia frederiksenii Yersinia intermedia Yersinia kristensenii
NA 58 NA NA 43 46 NA 51 52 NA NA NA NA 43 43 38 45 55 99 99 100 NA NA 41 NA 48 57 82–85 NA 56 NA NA NA NA 55–70 83 NA NA 85 57 57 57 NA
1
DeMoss & Moser (1969) Peel et al. (1999) von Graevenitz (1971) Moncla et al. (1991) Moncla et al. (1991) Moncla et al. (1991) Moncla et al. (1991) O’Hara et al. (2000) DeMoss & Moser (1969) O’Hara et al. (2000) O’Hara et al. (2000) O’Hara et al. (2000) O’Hara et al. (2000) Fukunaga et al. (2006) Mathesius et al. (2000) Schuurmans et al. (1956) Anton et al. (2002) Zhao et al. (2005) Rezwan et al. (2004) Rezwan et al. (2004) Rezwan et al. (2004) Rezwan et al. (2004) DeMoss & Moser (1969) Vancanneyt et al. (2006) Gerth et al. (1993) Socransky et al. (1969) Sakazaki (1968) Smith (1897) Lambert et al. (1998) Bieger & Crawford (1983) Lambert et al. (1998) Lambert et al. (1998) Lambert et al. (1998) Lambert et al. (1998) Sakazaki et al. (1963) Lambert et al. (1998) Lambert et al. (1998) Lambert et al. (1998) Tison et al. (1982), Dalsgaard et al. (1999) Schindler (1984), Sulakvelidze (2000) Sulakvelidze (2000), Merhej et al. (2008) Sulakvelidze (2000) Sulakvelidze (2000)
1 1 1 1 1 1 1 1 1 1 1/ 1 1 1 1 1 1/ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1/ 1/ 1 1 1/
Protein identity was obtained from a NCBI-BLASTP search using an Escherichia coli TnaA protein sequence, and sequence identity below 30% was discarded. NA, the genomic sequence is not available; 1, indole-positive strain in which indole production has been detected; , indole-negative strain that does not produce indole; 1/ , isolates from the same species in which some are indole positive and others are indole negative; ND, not determined.
many pathogenic bacteria such as Bacillus alvei, pathogenic E. coli, several Shigella strains, Enterococcus faecalis, and V. cholerae, can produce indole. Although the mechanism of indole biosynthesis in E. coli has been investigated over the past several decades (Newton & Snell, 1965; Botsford & DeMoss, 1971; Yanofsky et al., 1991), the real biological functions of indole have only 2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
recently started to be revealed. After Gerth et al. (1993) first suggested that indole was an autoinducer in Stigmatella aurantiaca (Gerth et al., 1993), many groups have reported diverse functions of indole. These include an extracellular signal in E. coli (Wang et al., 2001), drug resistance in E. coli (Hirakawa et al., 2005), plasmid stability in E. coli (Chant & Summers, 2007), virulence control in pathogenic E. coli FEMS Microbiol Rev 34 (2010) 426–444
429
Indole signaling in microbial community
(Anyanful et al., 2005; Hirakawa et al., 2009), and biofilm formation in E. coli (Di Martino et al., 2003; Lee et al., 2007b) and V. cholerae (Mueller et al., 2009). Owing to the limited information on indole-related phenotypes, indole was initially not considered to be a cell-to-cell signal molecule (Winzer et al., 2002). However, several lines of new evidence suggest that indole acts as an intercellular signal molecule (Chant & Summers, 2007; Lee et al., 2007a; Jayaraman & Wood, 2008; Monds & O’Toole, 2008; Ryan & Dow, 2008), which is discussed here in detail. Additionally, we address the fact that indole and AI-2 (one of the most studied signal molecules) have many similar as well as divergent characteristics in biosynthesis and function. Interestingly, indole signaling is dynamic in multispecies communities. For example, indole decreases the cell growth of a fungus, Aspergillus niger (Kamath & Vaidyanathan, 1990), attenuates the virulence in Pseudomonas aeruginosa (Lee et al., 2009a), and increases drug resistance in Salmonella enterica (Nikaido et al., 2008), which cannot produce indole. Additionally, many non-indole-producing bacteria and eukaryotes encode various oxygenases that can modify/ degrade indole and produce indole derivatives (Ensley et al., 1983; Rui et al., 2005; Wikoff et al., 2009). Indole derivatives are widely distributed in the human body, but their functions have not yet been revealed (Gillam et al., 2000; Crumeyrolle-Arias et al., 2008, 2009; Wikoff et al., 2009).
Therefore, indole is more important than originally thought, and many non-indole-producing species have developed specific mechanisms to metabolize indole and interfere with indole signaling. This review also discusses the perspectives of current indole research to study its bacterial physiology, pathogenesis, and ecology.
TnaA and indole biosynthesis In E. coli, indole is produced by tryptophanase (TnaA; EC 4.1.99.1), which can reversibly convert tryptophan into indole, pyruvate, and ammonia (Newton & Snell, 1965) (Fig. 1) in the tryptophan pathway in E. coli (Pittard, 1996; Lee et al., 2007b). However, no pathway for indole degradation is known for this bacterium (Chant & Summers, 2007). A comprehensive review of TnaA regarding its enzyme activity, structure, and mechanisms of action, can be found elsewhere (Snell, 1975). It has been long thought that bacteria utilize TnaA to synthesize tryptophan from indole as a carbon source (Gong & Yanofsky, 2002). However, the equilibrium of the reaction favors the production of indole from tryptophan (Tewari & Goldberg, 1994; Monds & O’Toole, 2008). In fact, the exogenous addition of indole (1–6 mM) does not increase the cell density because of its toxicity in E. coli (Chant & Summers, 2007). Escherichia coli, the most extensively studied organism for indole
Fig. 1. Indole biosynthesis and conceptual model of indole signaling in Escherichia coli. Spore formation is a phenotype of Stigmatella aurantiaca (Gerth et al., 1993; Stamm et al., 2005). The symbol ! indicates induction of gene expression or stimulation of a phenotype or transport, ? indicates repression of gene expression or repression of a phenotype, 2 indicates a possible interaction, and ? indicates a nonconclusive connection.
FEMS Microbiol Rev 34 (2010) 426–444
2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
430
biosynthesis, uses several mechanisms (repression, transcriptional attenuation, and feedback inhibition) to regulate the expression of tryptophan operon (trpABCDE) and tna operon (tnaCAB) in the tryptophan metabolism (Fig. 1) (Yanofsky et al., 1991; Gong & Yanofsky, 2002; Lee et al., 2007b). In tryptophan-deficient conditions, the expression of the trp operon is elevated, whereas the expression of the tna operon consisting of TnaC (24 amino acid leader peptide, previously called TnaL), TnaA (tryptophanase), and TnaB (permease) is repressed, as transcription-terminating factor (Rho)-dependent termination occurs in the tna operon. As a result, the expression of TnaA and TnaB and indole production are repressed when the level of tryptophan is low (Yanofsky et al., 1991; Gong & Yanofsky, 2002). In tryptophan-rich conditions, Rho-dependent transcriptional termination is eliminated so that indole production is elevated. Hence, extracellular tryptophan and other amino acids directly influence indole production (Gong & Yanofsky, 2002). Additionally, three permeases (Mtr, TnaB, and AroP) play different roles in tryptophan transport in different environment compositions and thus can directly influence the levels of indole (Fig. 1) (Yanofsky et al., 1991; Gong & Yanofsky, 2002). The Mtr permease is principally responsible for transporting indole, and the TnaB permease is critical for tryptophan uptake (Yanofsky et al., 1991). Although the production of tryptophan is costly (Yanofsky et al., 1991), cells still utilize the tryptophan pathway to produce and secrete indole in large quantities. Indole generated from tryptophan can be transported through cell membrane proteins (Fig. 1). For example, E. coli and V. cholerae can excrete indole up to 0.6 mM in a rich medium (Kobayashi et al., 2006; Lee et al., 2007b; Mueller et al., 2009). In E. coli, the efflux proteins AcrEF are partially responsible for exporting indole, as the indole excretion of the acrEF mutant was lower than that of its wild-type strain (Kawamura-Sato et al., 1999). The Mtr permease is primarily responsible for importing indole, as indole is not taken up by the mtr mutant (Yanofsky et al., 1991). However, it was recently suggested that indole could be directly diffused through the cell membrane due to its hydrophobic nature (Gaede et al., 2005). Hence, it is imperative to gain a clear understanding of how indole is imported and exported.
Indole-producing bacteria Many Gram-positive and Gram-negative bacteria encode a single copy of the tnaA gene in their chromosome and produce indole (Table 1). Although most organisms contain the tryptophan biosynthesis pathway, to date, only bacteria encoding tnaA can synthesize indole, and so far, no eukaryotic cells have been shown to produce indole. A NCBI-BLASTP search was performed using the E. coli TnaA protein. BLASTP 2.2.201 was used with a hit list size of 2000 and all of the 2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
J.-H. Lee & J. Lee
other parameters were the default parameters in the program. Protein sequences showing o 30% identity and the putative protein sequences of unknown function were discarded. As a result, more than 67 species contain TnaA homologues in a wide range of sequence identities (40–99% sequence identity with the E. coli TnaA in Table 1). Data available in the literature show that 54 bacterial species produce indole from these 67 species (Table 1). Further analysis of the literature shows that 31 more species produce indole, although the genomic sequence of the respective strains has not been reported (indicated as ‘NA’ in Table 1). In total, we found data supporting that, to date, 85 bacterial species have been shown to produce indole. Importantly, these include many pathogenic bacteria, for example Vibrio vulnificus (Dalsgaard et al., 1999), Haemophilus influenzae (Stull et al., 1995), Pasteurella multocida (Clemons & Gadberry, 1982), four Shigella strains (Rezwan et al., 2004), Klebsiella planticola (Liu et al., 1997), and Proteus vulgaris (DeMoss & Moser, 1969) (Table 1). Notably, several Grampositive strains including B. alvei (Hoch & Demoss, 1965) and E. faecalis (Schleifer et al., 1984) also produce indole. Intriguingly, several bacteria, such as Aeromonas salmonicida, Pseudovibrio sp., Shigella sonnei, Vibrio vulnificus and Yersinia kristensenii have lost the ability to synthesize indole, although these strains have a tnaA gene homologue in their chromosomes (Table 1). For example, unlike normal Shigella strains, some Shigella with point mutations, insertion, and/or deletion in the tna operon do not produce indole, possibly due to some adaptive advantage (Rezwan et al., 2004). Although speculative, some individuals may avoid the cost of producing indole by exploiting the signal from the local bacterial consortia in line with the kin selection model (Diggle et al., 2007b). Nevertheless, the main question remains as to why many bacteria produce indole in large quantities. Environmental factors controlling indole biosynthesis The accumulation of extracellular indole could be critically affected by environmental factors, such as the cell population, carbon sources, temperature, and pH. In fact, several lines of evidence support this possibility. First, the extracellular indole concentration is cell population density dependent where E. coli and V. cholerae start to produce indole in the early exponential phase. The concentration reaches a maximum level (up to 0.6 mM indole in a rich medium) in the stationary phase, and is stably maintained during the stationary phase (Kobayashi et al., 2006; Mueller et al., 2009). Secondly, in 1919, it was reported that glucose repressed indole biosynthesis (John & Wyeth, 1919). The catabolic repression of TnaA was confirmed because the transcription of tnaA gene was repressed during carbon FEMS Microbiol Rev 34 (2010) 426–444
431
Indole signaling in microbial community
limitation (Botsford & DeMoss, 1971). Additionally, the tnaAB operon was activated by catabolite regulation protein cyclic AMP complex in E. coli (Deeley & Yanofsky, 1982). Hence, E. coli produces a relatively large quantity of indole when its population is high and carbon source has dwindled (Fig. 1). Temperature and pH are also important environmental factors that affect indole biosynthesis in E. coli (Fig. 1). The gene expression of tnaAB was induced in E. coli by temperature shifting from 30 to 43 1C (Li et al., 2003), but E. coli lost the ability of indole biosynthesis at 44.5 1C (Bueschkens & Stiles, 1984). Also, the effect of indole signaling was more significant at a lower temperature (30 1C) compared with 37 1C in the control of gene expression, biofilm formation, and antibiotic resistance in E. coli (Lee et al., 2008). Additionally, a low pH inhibits indole production in E. coli
(John & Wyeth, 1919), and TnaA was one of the most induced proteins at pH 9.0 (Blankenhorn et al., 1999). Therefore, the environmental conditions such as cell population density, carbon source, temperature, and pH directly control the concentration of extracellular indole. It would be interesting to investigate whether the mechanism of indole biosynthesis in other indole-producing bacteria is similar to that in E. coli.
Functions of indole signal Indole plays diverse biological roles in several bacteria including spore formation, drug resistance, virulence, plasmid stability, and biofilm formation (Fig. 1, Table 2). Historically, it was first speculated that indole was a possible autoinducer, as indole induced a spore formation of S. aurantiaca
Table 2. Phenotypic changes affected by indole (or TnaA) in microorganisms Bacterium
Phenotype
Indole concentration used
References
Aspergillus niger
Inhibited cell growth
Kamath & Vaidyanathan (1990)
Enteropathogenic Escherichia coli O127:H6 Enterohemorrhagic Escherichia coli O157:H7 Enterohemorrhagic Escherichia coli O157:H7
TnaA is required for virulence against nematodes Increased secretion of virulencerelated EspA and EspB proteins Decreased motility, cell adherence to epithelial cells, chemotaxis, and biofilm formation Decreased biofilm formation
0–1.7 mM in Byrde’s medium at 28 1C 0.5 mM in LB at 37 1C 0–2.0 mM in LB medium at 37 1C
Hirakawa et al. (2009)
0–5.0 mM in LB at 37 1C
Bansal et al. (2007), Lee et al. (2007a)
1.0 mM in LB at 30 1C
Lee et al. (2007b)
0–6.0 mM in LB at 37 1C
Chant & Summers (2007)
0–2.0 mM in LB and LB glucose at 30 1C (more significant result) and 37 1C
Domka et al. (2006), Lee et al. (2007b, 2008)
5.0 mM in LB at 37 1C
Garbe et al. (2000)
0–1.25 mM in LB medium at 37 1C
Baca-DeLancey et al. (1999), Wang et al. (2001) Raffa & Raivio (2002), Hirakawa et al. (2005), Nishino et al. (2005) Di Martino et al. (2003) Lee et al. (2009a)
Escherichia coli ATCC25404, JM109, TG1, and XL1-Blue Escherichia coli BW25113 Escherichia coli BW25113
Escherichia coli JM109 Escherichia coli MC1061 Escherichia coli MC4100 and W3110 Escherichia coli S17-1 Pseudomonas aeruginosa
Salmonella enterica Stigmatella aurantiaca Vibrio cholerae
Enhanced plasmid stability and delayed cell division Decreased motility, cell division, biofilm formation, and acid resistance and increased drug resistance Inhibited cell growth due to oxidant toxicity Activated astD, gabT, and tnaB as an extracellular signaling molecule Increased drug resistance via BaeSR and CpxAR Increased biofilm formation Decreased virulence and increased antibiotic resistance and biofilm formation Enhanced drug resistance via RamA Induced a spore formation Activated genes involved in polysaccharide production, increased biofilm formation and grazing resistance to phagocytic eukaryote
2.0 mM in LB at 37 1C 0–1.25 mM in LB medium at 37 1C 0–1.0 mM in LB at 37 1C
2.0 mM in LB at 37 1C 0.1–2.0 mM in Casitone or tryptone medium at 32 1C 0–0.5 mM in LB at 37 1C
Anyanful et al. (2005)
Nikaido et al. (2008) Gerth et al. (1993), Stamm et al. (2005) Mueller et al. (2007), Mueller et al. (2009)
Aspergillus niger, Pseudomonas aeruginosa, and Salmonella enteric did not produce indole. The range of indole concentration used included a maximal value that did not indicate an optimal condition for the phenotypic changes.
FEMS Microbiol Rev 34 (2010) 426–444
2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
432
(myxobacteria, Table 1) in fruiting bodies (Gerth et al., 1993). The identity of indole as a possible extracellular signaling molecule was investigated in E. coli with an elegant genetic screen (Baca-DeLancey et al., 1999). As a result, four genes (astD, cysK, gabT, and tnaB) were shown to be activated by the accumulation of self-produced extracellular signals during the stationary phase (Baca-DeLancey et al., 1999). In a follow-up study, indole was confirmed as the extracellular signaling molecule required for the activation of astD, gabT, and tnaB (Wang et al., 2001). More recently, it has been shown that indole increases drug resistance by inducing intrinsic xenobiotic exporter genes (mdtEF and acrD) in E. coli, where indole acts via twocomponent signal transduction systems (BaeSR and CpxAR) (Hirakawa et al., 2005) (Fig. 1). Hence, it is possible that these two-component signal systems can be used as indole sensors. The result corroborates another study in which indole induces the expression of spy (spheroplast protein Y) gene via BaeSR and CpxAR (Raffa & Raivio, 2002; Nishino et al., 2005). Furthermore, it has been suggested that GadX (AraC-type transcription factor), Hfq (global regulator of sRNA function), and RpoS (stress and stationary phase sigma S) are essential for indole-induced mdtEF expression (Kobayashi et al., 2006). Hence, indole may interact with a variety of global regulators. Indole and the tnaA gene also affect the virulence of pathogenic bacteria. Tryptophanase activity is linked to the killing of nematodes by enteropathogenic E. coli, as tryptophanase activity is required for the full activation of the LEE1 promoter (Anyanful et al., 2005). Moreover, indole increases secretion of virulence-related EspA and EspB proteins (LEE4 gene products) and formation of attaching and effacing lesions in enterohemorrhagic E. coli (Hirakawa et al., 2009). In V. cholerae, indole and the tnaA gene increases grazing resistance to phagocytic eukaryote Dictyostelium discoideum, probably by inducing the virulenceassociated secretion proteins (Mueller et al., 2009). Additionally, among isolates of H. influenzae, most serotypes (94–100%) are indole-positive, compared with only 70–75% of harmless isolates. The result indicates that indole production is necessary but not sufficient for virulence to this strain (Martin et al., 1998). Indole enhances plasmid stability in E. coli (Chant & Summers, 2007). The study demonstrates that small noncoding RNAs from the E. coli plasmid ColE1 bind to TnaA and help preventing plasmid loss, and indole delays cell division (Chant & Summers, 2007). Also, indole in E. coli decreases acid resistance by repressing the acid-resistance genes such as gadABCEX, hdeABD, and ymgB (Lee et al., 2007b, c). Escherichia coli may turn off the acid resistance genes in the presence of indole in the weak basic gut flora, as acid resistance proteins are no longer needed after survival through the acidic stomach (Lee et al., 2007b). Additionally, 2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
J.-H. Lee & J. Lee
indole is a chemo-repellent and decreases motility, possibly due to cell division interference, whereas the eukaryotic hormones epinephrine and norepinephrine are a chemoattractant and increase motility in E. coli O157:H7 (Bansal et al., 2007). Furthermore, indole decreases cell adherence to epithelial cells, whereas epinephrine and norepinephrine increase cell adherence (Bansal et al., 2007). As bacterial adherence and colonization to epithelial cells are important for infection, it was hypothesized that these molecules would also differentially impact the bacterial virulence (Bansal et al., 2007). Additionally, the TnaA-dependent production of 3-nitrosoindole compounds takes place in E. coli under anaerobic growth, although the function of 3-nitrosoindole compounds in signaling has not been established (Kwon & Weiss, 2009). Moreover, indole increases drug resistance in S. enterica (non-indole-producing bacteria) by inducing the efflux pump system (AcrAB) via the transcriptional regulator RamA that belongs to the AraC transcriptional activator family (Nikaido et al., 2008). The RamA-binding sites are located in the upstream regions of acrAB and tolC (Nikaido et al., 2008). Also, indole decreases the production of virulence factors in P. aeruginosa (non-indole-producing bacteria) by altering gene expression, in contrast to AHLs; for example, indole represses genes encoding the mexGHIopmD multidrug efflux pump, phz operon, pqs operon, pch operon, and pvd operon, whereas AHLs induce these genes (Lee et al., 2009a). Therefore, indole influences several phenotypes of non-indole-producing bacteria as well as indole-producing bacteria.
Indole and biofilm formation Indole controlling the biofilm formation is a key example of group behavior in E. coli (Di Martino et al., 2003; Domka et al., 2006; Lee et al., 2007b), V. cholerae (Mueller et al., 2007, 2009), and P. aeruginosa (Lee et al., 2009a). Initially, it was reported that E. coli S17-1 tnaA mutant reduced biofilm formation and indole restored the tnaA biofilm (Di Martino et al., 2003) in Luria–Bertani (LB) medium at 37 1C (Di Martino et al., 2002, 2003). In contrast, indole decreased the biofilm formation of nine nonpathogenic E. coli (BW25113, BW25113 bhsA, BW25113 bssR, BW25113 bssS, BW25113 tnaA, ATCC25404, JM109, TG1, and XL1-Blue) as well as pathogenic E. coli O157:H7 (Domka et al., 2006; Bansal et al., 2007; Lee et al., 2007b; Zhang et al., 2007) in LB glucose medium at 37 1C or in LB at 30 1C. The latter studies demonstrated that indole decreases E. coli biofilms by reducing motility (Domka et al., 2006; Bansal et al., 2007; Lee et al., 2007b), repressing acid resistance genes (Lee et al., 2007b), reducing chemotaxis (Bansal et al., 2007), and reducing attachment to epithelial cells (Bansal et al., 2007). This discrepancy of indole effects on biofilm formation FEMS Microbiol Rev 34 (2010) 426–444
433
Indole signaling in microbial community
between the studies of Di Martino et al. (2002, 2003) and others (Domka et al., 2006; Bansal et al., 2007; Lee et al., 2007b; Zhang et al., 2007) could be caused by the different experimental conditions and different E. coli strains used (Table 2). For example, the presence of glucose turns off endogenous indole production (Botsford & DeMoss, 1971) so that the effect of exogenous indole may be more significant in the presence of glucose because it reduces background indole (Lee et al., 2007b). Also, the effects of indole on biofilm formation, antibiotic resistance, cell division, and the ability to control gene expression are more significant at temperatures below 37 1C (Lee et al., 2008). Therefore, there is the question of why indole decreases its own biofilm formation in E. coli. A possible explanation can be found in the known biology of V. cholera, in which quorum-sensing molecules negatively regulate biofilm formation to redirect V. cholera growth to a less cell-dense environment (Nadell et al., 2008). In contrast to E. coli, V. cholerae tnaA mutant resulted in decreased biofilm formation in LB medium at 37 1C, and the addition of indole complemented the tnaA biofilm (Mueller et al., 2007). Indole activates the genes involved in Vibrio polysaccharide (VPS) production, which is essential for V. cholerae biofilm formation (Mueller et al., 2009). Hence, it appears indole positively influences the biofilm formation of V. cholerae (Mueller et al., 2007), whereas other quorumsensing molecules negatively regulate its biofilm (Hammer & Bassler, 2003; Nadell et al., 2008). It was also reported that indole increased the biofilm formation of the non-indoleproducing P. aeruginosa (Lee et al., 2009a). Although many bacteria produce indole (Table 1), indole signaling has only been investigated in a few bacteria, mainly E. coli, S. aurantiaca, and V. cholerae. Hence, it would be interesting to investigate indole signaling in other indole-producing bacteria (Table 1). Several transcriptomics studies have demonstrated that indole regulates the expression of many genes in E. coli (Nishino et al., 2005; Bansal et al., 2007; Lee et al., 2007b; Lee et al., 2008), P. aeruginosa (Lee et al., 2009a), and V. cholerae (Mueller et al., 2009). Although whole-transcriptome profiling may not reveal some aspects of heterogeneous cells such as biofilm cells (An & Parsek, 2007), DNA microarrays can be used as a starting point toward a better understanding of indole signaling.
Indole as an intercellular signal molecule It has been controversial whether indole is an intercellular signal molecule or not. A number of criteria for the requirement of a quorum-sensing signal molecule have been suggested. Winzer et al. (2002) suggested four criteria, which were satisfied for indole as followed: 1. The putative signal must be produced during a specific stage. Indole is produced primarily in the stationary phase (Wang et al., 2001; Mueller et al., 2009). FEMS Microbiol Rev 34 (2010) 426–444
2. The putative signal must accumulate extracellularly and be recognized by a specific receptor. The chemical nature of indole is well known and in most cases of indole regulation, chemical complementation was demonstrated, where indole accumulates during the stationary phase and is a known extracellular signal (Wang et al., 2001; Mueller et al., 2009). This receptor is exported by AcrEF (Kawamura-Sato et al., 1999) and imported by Mtr (Yanofsky et al., 1991). Moreover, several possible indole receptors are currently being investigated (such as SdiA and two-component systems); this matter will be discussed more in detail in the next section. 3. The putative signal must accumulate and generate a concerted response. Indole has been shown to control spore formation (Gerth et al., 1993) and biofilm (Lee et al., 2007b; Mueller et al., 2009). 4. Importantly, the putative signal must elicit a response that extends beyond the physiological changes required to metabolize or detoxify the signal. Indole has been shown to control virulence (Hirakawa et al., 2009), biofilms (Lee et al., 2007b; Mueller et al., 2009), and plasmid stability (Chant & Summers, 2007), which are not related to indole metabolism. Therefore, according to these criteria, indole has the potential to be a quorum-sensing molecule (Chant & Summers, 2007; Lee et al., 2007a). As the above four criteria only fit the canonical quorumsensing signals such as AHLs, Monds & O’Toole (2008) added two more criteria that are more generally applicable and of practical value: 1. The physiologically relevant concentration of the signal required for the phenotypic changes is not toxic to the cell. Escherichia coli and V. cholerae produce up to 0.6 mM indole that is not toxic to the cell (Chant & Summers, 2007; Mueller et al., 2009) and control many phenotypes at that physiological concentration as outlined in the previous section. 2. The signal network is adaptive at the level of the community. Although hard to prove due to the difficulty of evolutionary experiments, we hypothesized that the intercellular signal indole may be beneficial to the microbial community even though the production of indole is costly to the individual. For example, indole increased plasmid stability (Chant & Summers, 2007), drug resistance (Hirakawa et al., 2005), and grazing resistance to phagocytic eukaryote D. discoideum (Mueller et al., 2009) in indole-producing bacteria E. coli and V. cholerae. In contrast, in non-indole-producing bacteria, indole decreased cell growth of a fungus (Kamath & Vaidyanathan, 1990) and virulence of P. aeruginosa by interfering with the quorum-sensing system (Lee et al., 2009a). Hence, we speculate that indole-producing bacteria may use indole to survive against other bacteria and eukaryotes. 2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
434
Indole-binding regulatory proteins Canonical cell-to-cell signal systems, such as AHLs, include a signal synthase and a cognate transcriptional regulator such as LuxR-type proteins that bind to the accumulated signal molecules (Fuqua et al., 1994; Patankar & Gonzalez, 2009). Unlike the AHL systems, there is no LuxR-type protein that directly binds to indole or AI-2. Intriguingly, the E. coli LuxR-homologue SdiA is involved in indole signaling (Lee et al., 2007b, 2008, 2009b), although E. coli does not naturally produce AHLs (Ahmer, 2004). In these studies, SdiA was necessary for indole signaling in E. coli, as in the sdiA mutant, the effect of indole on biofilm formation was lost, and no significant changes of gene expression with a response to indole were shown (Lee et al., 2008). Additionally, the mutation of SdiA by the directed evolution influenced the indole production and biofilm formation in E. coli (Lee et al., 2009b). However, so far, there is no proof of the direct binding of indole and SdiA, and how indole and SdiA interact and work is still unclear and remains to be investigated further. Indole also acts on the sensor kinases, BaeS and CpxA, and interacts with GadX (a transcriptional activator for acid resistance) to control drug resistance in E. coli (Hirakawa et al., 2005). In V. cholerae, indole can directly interact with the RNA polymerase regulator protein DksA, the dnaK suppressor protein and indole activates the genes involved in VPS production through the DksA and the VPS regulator, VpsR, a distant homologue of SdiA (Mueller et al., 2009). In S. aurantiaca, indole binds to pyruvate kinase (PykA) to induce spore formation in the fruiting bodies (Stamm et al., 2005). Hence, it is interesting to find indole-interacting proteins in other bacterial species using the indole affinity matrix to identify indole binding PykA of S. aurantiaca (Stamm et al., 2005).
Comparison of AI-2 signaling and indole signaling Bacteria often produce multiple signal molecules and differentially respond to each signal molecule (Waters & Bassler, 2006; Williams & Ca´ mara, 2009). To date, the only signal molecule shared by both Gram-positive and Gram-negative bacteria is AI-2, which is synthesized by the enzyme LuxS (Xavier & Bassler, 2003; Hardie & Heurlier, 2008). The AI-2 system is found in over 55 species and E. coli senses AI-2 that is produced by Vibrio harveyi to assess any changes in its cell population in batch culture on rich laboratory medium (Xavier & Bassler, 2005b), which suggests that AI-2 is an interspecies signal molecule (Xavier & Bassler, 2003; Vendeville et al., 2005). AI-2 is one of the most studied quorumsensing signals because it is involved in the regulation of bioluminescence and virulence-associated traits in Vibrio (Xavier & Bassler, 2003; Xavier & Bassler, 2005b). AI-2 2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
J.-H. Lee & J. Lee
(Fig. 2) binds to its periplasmic receptor LuxP and interacts with a histidine kinase LuxQ in V. harveyi (Neiditch et al., 2005), and AI-2 in E. coli is internalized by the Lsr ABC transporter (Xavier & Bassler, 2005a). Unlike AHL systems, there is no report of a LuxR-type regulator that binds directly to either AI-2 or indole. Hence, AI-2 and indole signaling may not require a direct binding of LuxR-type protein. As shown in Table 1, 85 species of both Gram-positive and Gram-negative bacteria produce indole, which supports a possible role of indole as an interspecies signal. Thus, in addition to AI-2, indole is another signal molecule shared by both Gram-positive and Gram-negative bacteria. Notably, E. coli, Photorhabdus luminescens, Porphyromonas gingivalis, Rhizobium leguminosarum bv., Shigella flexneri, V. cholerae, and V. vulnificus, produce both AI-2 and indole (Table 1). Additionally, V. harveyi and Vibrio parahaemolyticus produce multiple signal molecules, such as HAI-1 (an AHL), CAI-1, AI-2 (Waters & Bassler, 2006), and even indole (Table 1). Hence, bacteria may use various signaling mechanisms to gather, process and transduce diverse environmental information, such as pH, temperature, nutrient availability, osmolarity, and cell density to survive in dynamic microbial communities (Xavier & Bassler, 2003; Hardie & Heurlier, 2008; Williams & Ca´ mara, 2009). Interestingly, indole and AI-2 have divergent characteristics for the biosynthesis of molecules in various environmental conditions (Table 3). AI-2 accumulation is induced in the presence of glucose (Surette & Bassler, 1998), whereas indole synthesis is inhibited in the presence of glucose (John & Wyeth, 1919; Botsford & DeMoss, 1971). AI-2 accumulation was maximal at a low pH (pH 5.0) (Surette & Bassler, 1999), whereas indole synthesis was inhibited at pH levels below 4.3 (John & Wyeth, 1919) and TnaA was one of the most induced protein at pH 9.0 in E. coli (Blankenhorn et al., 1999). AI-2 exists transiently during the exponential phase and is a heat-labile compound (Surette & Bassler, 1998), while indole is stably maintained during the stationary phase and is heat stable in E. coli (Kobayashi et al., 2006) and V. cholerae (Mueller et al., 2009). Furthermore, the signal modifications are different in that AI-2 can be phosphorylated by LsrK kinase and further degraded by LsrF and LsrG (Xavier & Bassler, 2005a), whereas indole can be oxidized by oxygenases from other species (Gillam et al., 2000; Lee et al., 2007a), but is not degraded by its own species (Chant & Summers, 2007). In E. coli (Table 3), exogenously supplied AI-2 increases biofilm formation at 37 1C (Gonza´ lez Barrios et al., 2006), whereas indole decreases biofilm formation more significantly at 30 1C than at 37 1C (Lee et al., 2007b, 2008). AI-2 is chemo-attractant and increases motility and cell adherence to epithelial cells (Bansal et al., 2008), whereas indole is chemo-repellent and decreases swimming motility and cell FEMS Microbiol Rev 34 (2010) 426–444
435
Indole signaling in microbial community
Fig. 2. Structure of indole-related compounds. Indole, isatin, 5-hydroxyindole, 7-hydroxyindole, indoxyl sulfate, and indole-3-propionic acid are derived from enteric bacteria. Indole-3-acetic acid, indole-3-carbinol, 3-indolylacetonitrile, and 3,3 0 -diindolymethane are plant-derived compounds. Epinephrine, serotonin, and melatonin are animal hormones. Offsetting of AI-2 is used due to little structural similarity. Indole motifs are in bold.
adherence to epithelial cells (Bansal et al., 2007). The addition of (S)-4,5-dihydroxy-2,3-pentanedione (DPD, AI2 precursor) to the AI-2-deficient (luxS) mutant leads to more extensive differential gene expression at 37 1C than at 30 1C, whereas the addition of indole to the indole-deficient (tnaA) mutant leads to more extensive differential gene expression at 30 1C than at 37 1C (Lee et al., 2008). As a result, DPD induces the expression of uracil-related genes (carAB, pyrLBI, pyrC, pyrD, pyrF, upp, and uraA) at 37 1C, but no induction at 30 1C, whereas indole represses the expression of the same uracil-related genes at 30 1C, but not at 37 1C (Lee et al., 2008). Also, the indole-derivative isatin (Fig. 2) seems to mimic AI-2 in stimulating biofilm formation (Lee et al., 2007a) because both AI-2 and isatin induce the same flagella genes and increase motility, and isatin decreases the indole production (Ren et al., 2004; Lee et al., 2007a; Bansal et al., 2008). Therefore, bacterial species may utilize different signaling systems (or redundant signal molecules) to sense diverse environmental conditions and to adapt in a new environment. Indole and AI-2 signalings seem to be intertwined. Understanding how AI-2 and indole signaling are connected to each other is challenging but stimulating. In other strains, V. harveyi uses shared regulatory components to discriminate between multiple autoinducers, and LuxR controls the quorum-sensing-regulated genes (Waters & Bassler, 2006). Additionally, multiple quorum-sensing sysFEMS Microbiol Rev 34 (2010) 426–444
tems in P. aeruginosa are integrated and subject to the prevailing environmental conditions (Williams & C´amara, 2009). In E. coli, SdiA (a LuxR homologue) recognizes AHLs, although E. coli cannot produce AHLs (Yao et al., 2006). The indole signaling mechanism requires SdiA (Lee et al., 2007b; Lee et al., 2008) and the directed-evolution of the SdiA protein influences the production of indole (Lee et al., 2009b). It was also suggested that AI-2 might work together with SdiA (DeLisa et al., 2001). Therefore, it is possible that SdiA may be associated with multiple signals, such as AHLs, AI-2, and indole.
Interference of indole signaling In environmental niches, bacteria coexist in multispecies communities with other bacteria and their hosts, while competing for resources and spaces. Signal molecules can be interfered intrinsically and extrinsically by signal degradation, inhibition of signal molecule biosynthesis, the reduction of receptor proteins, and structural modification (Zhang & Dong, 2004). Although indole is stably present during the stationary phase in indole-producing E. coli and V. cholerae, many non-indole-producing bacteria can metabolize indole through some dioxygenases and monooxygenases found in microbial communities. For example, Pseudomonas putida PpG7 (Ensley et al., 1983), Ralstonia pickettii PKO1 (Fishman et al., 2005), Pseudomonas 2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
436
J.-H. Lee & J. Lee
Table 3. Comparison of AI-2 and indole signaling
Producing strains Signal synthase Transporter
Binding receptor Production and stability in E. coli
Distinctive functions in E. coli
AI-2
Indole
Both Gram positive and Gram negative (Xavier & Bassler, 2003) LuxS in cell density-dependent manner (Surette & Bassler, 1998) LsrACDB (ABC transporter) in E. coli (Xavier & Bassler, 2005a)
Both Gram positive and Gram negative (Table 1)
LuxPQ in V. harveyi (Neiditch et al., 2005) Induced in the presence of glucose (Surette & Bassler, 1999) Induced at low pH (Surette & Bassler, 1999) Transiently present during the exponential phase (Surette & Bassler, 1998) Heat labile (Surette & Bassler, 1998) Self-metabolized by own enzymes (Xavier & Bassler, 2005a) ´ Increased biofilm formation (Gonzalez Barrios et al., 2006) Chemo-attractant (Bansal et al., 2008) Increased cell motility (Bansal et al., 2008) Increased cell adherence to eukaryotic cells (Bansal et al., 2008) High differential gene expression at 37 1C (Lee et al., 2008) Induced UMP synthesis genes at 37 1C (Lee et al., 2008)
TnaA in cell density-dependent manner (Newton & Snell, 1965) Mtr and AcrEF in E. coli (Yanofsky et al., 1991; Kawamura-Sato et al., 1999). Possibly direct diffusion (Gaede et al., 2005) PykA in S. aurantiaca (Stamm et al., 2005) Repressed in the presence of glucose (John & Wyeth, 1919) Repressed at low pH (John & Wyeth, 1919) Stably present during the stationary phase (Kobayashi et al., 2006) Heat stable (no degradation even after autoclaving) Metabolized by oxygenases from other bacteria (Lee et al., 2007a) Decreased biofilm formation (Lee et al., 2007a) Chemo-repellent (Bansal et al., 2007) Decreased cell motility (Lee et al., 2008) Decreased cell adherence to eukaryotic cells (Bansal et al., 2007) High differential gene expression at 30 1C (Lee et al., 2008) Repressed UMP synthesis genes at 30 1C (Lee et al., 2008)
UMP, uridine monophosphate.
mendocina KR1 (Tao et al., 2004), and Burkholderia cepacia G4 (Rui et al., 2005) readily convert indole to oxidized indole compounds such as 2-hydroxyindole, 3-hydroxyindole, 4-hydroxyindole, isatin, indigo, isoindigo, and indirubin (Rui et al., 2005). In some cases, non-indole-producing bacteria can utilize indole as a carbon source. For example, P. aeruginosa Gs isolated from mangrove sediment (Yin et al., 2005) and Pseudomonas sp. ST-200 from soil (Doukyu & Aono, 1997) grow on indole and thus can remove indole from the environment. A previous report showed that indole inhibited cell growth of a fungus, A. niger, that could degrade indole (Kamath & Vaidyanathan, 1990). Indole enhances the virulence of enterohemorrhagic E. coli (Anyanful et al., 2005; Hirakawa et al., 2009). Moreover, indole diminishes the virulence of P. aeruginosa that may threaten E. coli and its host (Lee et al., 2009a), whereas P. aeruginosa can easily degrade indole (Lee et al., 2009a). In a dual species culture of E. coli and Pseudomonas fluorescens expressing toluene-omonooxygenase that can oxidize indole, the presence of toluene-o-monooxygenase decreases the level of indole and controls biofilm formation of E. coli (Lee et al., 2007b). Hence, non-indole-producing bacteria have developed a defense system to cope with indole; therefore, competition 2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
and interference for indole signal appear to be intense in multispecies bacterial consortia. A proposed model of interference for indole signaling in an animal intestine is shown in Fig. 3. A variety of animal species contain indole-positive bacteria in their intestinal tract (DeMoss & Moser, 1969). The concentration of fecal indole in the average Asian woman is between 10 and 30 mg g1 dried stool depending on her diet (Fujisawa et al., 2006; Ishikado et al., 2007), which indicates that gut bacteria produce copious amounts of indole in humans. Nonindole-producing bacteria with oxygenases can oxidize indole into diverse oxidized indoles, which can be further dimerized into insoluble indigoid compounds (Rui et al., 2004) (Fig. 3). Hence, some bacterial oxygenases have been proposed to have evolved to regulate the concentration of indole signal by removing it via precipitation (Lee et al., 2007b). Indole generated from gut bacteria can be absorbed into the human body in substantial amounts and cytochrome P450 enzymes can oxidize indole into a variety of oxidized indoles (Gillam et al., 2000). Moreover, metabolomic analysis reveals that the production of several indole metabolites in mice blood, such as indolyl sulfate and indole-3-propionic acid, is completely dependent on gut microbial communities (Wikoff et al., 2009). FEMS Microbiol Rev 34 (2010) 426–444
437
Indole signaling in microbial community
Fig. 3. Hypothetical model for interference of indole signal in an animal intestine. Indole-producing bacteria produce indole that can be oxidized by diverse oxygenases including P450 from other bacteria and animal cells. Oxidized indole can be further dimerized into insoluble indigoid compounds for precipitation or can be transported into animal cells.
Roles of indole derivatives in multispecies community Bacteria-originated indole derivatives may play biological roles in microbial consortia as well as eukaryotic cells. Oxidized indole derivatives showed distinctive effects on biofilm formation, cell motility, and gene expression in the pathogenic E. coli O157:H7 (Lee et al., 2007a). For example, isatin increases biofilm formation by repressing indole production and increasing motility, whereas 5-hydroxyindole and 7-hydroxyindole (Fig. 2) are more potent in decreasing biofilm formation of E. coli O157:H7 compared with indole (Lee et al., 2007a). Also, 7-hydroxyindole diminishes the virulence of P. aeruginosa by repressing quorum-sensing-related genes in a manner opposite that of AHLs and decreases swarming motility and colonization of P. aeruginosa in guinea pigs (Lee et al., 2009a). Hence, 7-hydroxyindole (Lee et al., 2009a) could potentially be used for antivirulence therapies (Lesic et al., 2007; Cegelski et al., 2008), which are also known as antipathogenic drugs (Rasmussen & Givskov, 2006). Antivirulence compounds are an important tool for fighting infectious diseases because, unlike antimicrobials, antivirulence compounds such as 7-hydroxyindole do not affect cell growth (Lee et al., 2009a), so there is less chance of developing resistance (Hentzer et al., 2002; Lesic et al., 2007). Many plants have developed bacterial defense systems that interfere with bacterial cell signaling using signaling inhibitors, such as halogenated furanones from Delisea pulchra (Hentzer et al., 2003) and other quorum-sensing inhibitors from carrots, garlic, chili, and water lily (Rasmussen & Givskov, 2006). Natural indole-like compounds also influence bacterial physiology. For example, indole-3carbinol and 3,3 0 -diindolylmethane (Fig. 2) from cruciferous vegetables show antimicrobial, antiviral, and anticancer FEMS Microbiol Rev 34 (2010) 426–444
activity (Higdon et al., 2007; Fan et al., 2009). As a preliminary, indolylacetonitrile (Fig. 2) inhibited biofilm formation of E. coli O157:H7 up to 10-fold in a dose–response manner (0, 10, 30, 75, and 100 mg mL1) without affecting the cell growth (J.-H. Lee & J. Lee, unpublished data). Additionally, a synthetic indole derivative (CBR4830) has been shown to inhibit P. aeruginosa growth through a multidrug efflux pump, mexAB-oprM (Robertson et al., 2007). These results suggest that indole derivatives (natural and synthetic) are potential natural biofilm inhibitors as well as antimicrobial agents to control pathogenic bacteria. Moreover, indole and indole derivatives may have some biological functions in the human body. Humans and intestinal bacteria have developed a commensal relationship over a long period, and some bacteria are crucial for nutrient assimilation and are beneficial to the human immune system (Hooper & Gordon, 2001; Wikoff et al., 2009). Recently, an MS-based metabolomics study demonstrated that the production of indoxyl sulfate and indole-3-propionic acid in animal blood completely depends on enteric bacteria (Fig. 2) (Wikoff et al., 2009). Indole-3-propionic acid is a powerful antioxidant (more potent than melatonin) and a possible treatment for Alzheimer’s disease (Chyan et al., 1999). Furthermore, gut bacteria-derived isatin (Fig. 2) was detected in blood, peripheral tissues, urine, and even brain up to a relative high level (70 mM), although its biological targets remain poorly characterized (Crumeyrolle-Arias et al., 2009). Additionally, 5-hydroxyindole (Fig. 2) produced from gut bacteria was detected in blood, plasma, and brain, where the concentration of 5-hydroxyindole fluctuated photoperiodically, although its role is unknown (Crumeyrolle-Arias et al., 2008). The study of how gut epithelial cells react to indole and indole derivatives is of interest. Recently, it was shown that 2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
438
indole significantly affects the gene expression of epithelial cell-junction and cytokines (Bansal et al., 2009). Interestingly, bacterial signal indole and eukaryotic hormones, epinephrine and norepinephrine, exert divergent effects on bacterial physiology of enterohemorrhagic E. coli (Bansal et al., 2007). Therefore, indole and indole derivatives (Fig. 2) may influence the balance of microbial flora in the human body.
Concluding remarks We demonstrate here that both Gram-positive and Gramnegative bacteria including many pathogens produce a relatively large quantity of indole (Table 1) in spite of the high metabolic cost, and that indole represents a new class of intercellular signal molecules having diverse biological functions in ecological niches. To date, indole signaling has been studied using only few strains, and it offers an exciting challenge to investigate the roles of indole in various species including human cells. More importantly, further studies are essential to determine the genetic regulatory mechanism of indole signaling, which is still elusive. As indole biosynthesis can be influenced by several environmental factors (Fig. 1, Table 3), the experimental conditions are critical in the study of indole signaling (Table 2). For example, if one wants to mimic the high indole environment of the large intestine, a glucose-free medium should be chosen. Additionally, a physiologically relevant concentration of indole is required to study indole signaling (note that E. coli and V. cholerae produce extracellular indole up to 0.6 mM in a rich medium). A high concentration of indole (above 2 mM) apparently decreases cell growth in E. coli (Chant & Summers, 2007; Lee et al., 2009b), probably due to the blocking of cell division (Chant & Summers, 2007; Lee et al., 2009b), the disruption of the bacterial envelope (Raffa & Raivio, 2002), and/or oxidant toxicity (Garbe et al., 2000). Consequently, a high dose of indole may affect the overall cellular metabolism and may lead to a pleiotropic effect. Additionally, it is difficult to measure the environmental concentration of indole in dynamic microbial niches, especially inside a biofilm and in a multispecies bacterial consortium. Therefore, a wide range of indole concentrations should be carefully investigated. For example, AI-2 concentration critically influences (increases or decreases) biofilm formation of dual-species of Actinomyces naeslundii T14V and Streptococcus oralis 34 (Rickard et al., 2006). As microbial communities dynamically react with multiple signal molecules such as AHLs, AI-2, and indole, temporal study of signal molecules is necessary instead of a single time point study. It was hypothesized that multiple AHL signals in P. aeruginosa were believed to regulate the gene expression in a specific temporal order (Schuster et al., 2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
J.-H. Lee & J. Lee
2003), and a temporal transcriptomic study of AI-2 signal showed the temporal expression of virulence genes (Bansal et al., 2008). Table 3 indicates a possible interconnection between AI-2 and indole, which suggests that bacteria may utilize multiple signals to respond dynamically to diverse environmental stimuli. Many bacteria may use the indole signal to thrive over other bacteria in multispecies communities, whereas other bacteria have acquired diverse defense systems, such as monooxygenases, dioxygenases, and P450 family, to metabolize indole. Furthermore, animals possibly utilize indole derivatives originated from gut microbial communities for their immune systems (Wikoff et al., 2009). Currently, there is much interest in ‘postbiotics’ as well as ‘probiotics’ as new therapeutic strategies (Neish, 2009). Postbiotics are defined as the supplementation of the human gut with bacteria products such as butyrate and other short-chain fatty acids (Neish, 2009). Indole derivatives have a potential as postbiotics, as indole-3-propionic acid is a powerful antioxidant (Wikoff et al., 2009), and 7-hydroxyindole diminishes virulence and colonization of pathogenic P. aeruginosa (Lee et al., 2009a). To develop a new therapeutic agent, it will be necessary to screen more natural and synthetic indole derivatives that are nontoxic and cannot be easily metabolized by pathogens. Indole signaling appears to be important in microbial consortia and may influence the digestive and immune system in humans. Research into indole signaling has recently been begun and much remains to be investigated. Understanding indole signaling will help develop effective antimicrobial or antivirulence strategies and biotechnology applications.
Acknowledgements This research was supported by the Yeungnam University research grant (to J.L.). J.-H.L. was supported by the Brain Korea 21 Project from the Ministry of Education and Human Resources, Korea. We would like to thank Thomas K. Wood (Texas A & M University) for his help in the study of indole signaling.
References Ahmer BM (2004) Cell-to-cell signalling in Escherichia coli and Salmonella enterica. Mol Microbiol 52: 933–945. Allison MJ, Dawson KA, Mayberry WR & Foss JG (1985) Oxalobacter formigenes gen. nov., sp. nov.: oxalate-degrading anaerobes that inhabit the gastrointestinal tract. Arch Microbiol 141: 1–7. Alves MS, Dias RC, de Castro AC, Riley LW & Moreira BM (2006) Identification of clinical isolates of indole-positive and indolenegative Klebsiella spp. J Clin Microbiol 44: 3640–3646.
FEMS Microbiol Rev 34 (2010) 426–444
439
Indole signaling in microbial community
Amandi A, Hiu SF, Rohovec JS & Fryer JL (1982) Isolation and characterization of Edwardsiella tarda from fall chinook salmon (Oncorhynchus tshawytscha). Appl Environ Microb 43: 1380–1384. An D & Parsek MR (2007) The promise and peril of transcriptional profiling in biofilm communities. Curr Opin Microbiol 10: 292–296. Anton J, Oren A, Benlloch S, Rodriguez-Valera F, Amann R & Rossello-Mora R (2002) Salinibacter ruber gen. nov., sp. nov., a novel, extremely halophilic member of the bacteria from saltern crystallizer ponds. Int J Syst Evol Micr 52: 485–491. Anyanful A, Dolan-Livengood JM, Lewis T et al. (2005) Paralysis and killing of Caenorhabditis elegans by enteropathogenic Escherichia coli requires the bacterial tryptophanase gene. Mol Microbiol 57: 988–1007. Baca-DeLancey RR, South MM, Ding X & Rather PN (1999) Escherichia coli genes regulated by cell-to-cell signaling. P Natl Acad Sci USA 96: 4610–4614. Bansal T, Englert D, Lee J, Hegde M, Wood TK & Jayaraman A (2007) Differential effects of epinephrine, norepinephrine, and indole on Escherichia coli O157:H7 chemotaxis, colonization, and gene expression. Infect Immun 75: 4597–4607. Bansal T, Jesudhasan P, Pillai S, Wood TK & Jayaraman A (2008) Temporal regulation of enterohemorrhagic Escherichia coli virulence mediated by autoinducer-2. Appl Microbiol Biot 78: 811–819. Bansal T, Alaniz RC, Wood TK & Jayaraman A (2009) The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. P Natl Acad Sci USA DOI: 10.1073/pnas.0906112107. Bassler BL (1999) How bacteria talk to each other: regulation of gene expression by quorum sensing. Curr Opin Microbiol 2: 582–587. Behrend C & Heesche-Wagner K (1999) Formation of hydrideMeisenheimer complexes of picric acid (2,4, 6-trinitrophenol) and 2,4-dinitrophenol during mineralization of picric acid by Nocardioides sp. strain CB 22-2. Appl Environ Microb 65: 1372–1377. Bieger CD & Crawford IP (1983) Tryptophan biosynthesis in the marine luminous bacterium Vibrio harveyi. J Bacteriol 153: 884–894. Blankenhorn D, Phillips J & Slonczewski JL (1999) Acid- and base-induced proteins during aerobic and anaerobic growth of Escherichia coli revealed by two-dimensional gel electrophoresis. J Bacteriol 181: 2209–2216. Booth EV & McDonald S (1971) A new group of enterobacteria, possibly a new Citrobacter sp. J Med Microbiol 4: 329–336. Botsford JL & DeMoss RD (1971) Catabolite repression of tryptophanase in Escherichia coli. J Bacteriol 105: 303–312. Bueschkens DH & Stiles ME (1984) Escherichia coli variants for gas and indole production at elevated incubation temperatures. Appl Environ Microb 48: 601–605. Carlier JP, K’Ouas G, Bonne I, Lozniewski A & Mory F (2004) Oribacterium sinus gen. nov., sp. nov., within the family
FEMS Microbiol Rev 34 (2010) 426–444
‘Lachnospiraceae’ (phylum Firmicutes). Int J Syst Evol Micr 54: 1611–1615. Cegelski L, Marshall GR, Eldridge GR & Hultgren SJ (2008) The biology and future prospects of antivirulence therapies. Nat Rev Microbiol 6: 17–27. Chant EL & Summers DK (2007) Indole signalling contributes to the stable maintenance of Escherichia coli multicopy plasmids. Mol Microbiol 63: 35–43. Christiansen N & Ahring BK (1996) Introduction of a de novo bioremediation activity into anaerobic granular sludge using the dechlorinating bacterium DCB-2. Antonie van Leeuwenhoek 69: 61–66. Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J & Pappolla MA (1999) Potent neuroprotective properties against the Alzheimer b-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid. J Biol Chem 274: 21937–21942. Clemons KV & Gadberry JL (1982) Increased indole detection for Pasteurella multocida. J Clin Microbiol 15: 731–732. Comella N & Grossman AD (2005) Conservation of genes and processes controlled by the quorum response in bacteria: characterization of genes controlled by the quorum-sensing transcription factor ComA in Bacillus subtilis. Mol Microbiol 57: 1159–1174. Crumeyrolle-Arias M, Tournaire MC, Rabot S, Malpaux B & Thi´ery JC (2008) 5-Hydroxyoxindole, an indole metabolite, is present at high concentrations in brain. J Neurosci Res 86: 202–207. Crumeyrolle-Arias M, Buneeva O, Zgoda V et al. (2009) Isatin binding proteins in rat brain: in situ imaging, quantitative characterization of specific [3H]isatin binding, and proteomic profiling. J Neurosci Res 87: 2763–2772. Cumberbatch N, Gurwith MJ, Langston C, Sack RB & Brunton JL (1979) Cytotoxic enterotoxin produced by Aeromonas hydrophila: relationship of toxigenic isolates to diarrheal disease. Infect Immun 23: 829–837. Dalsgaard I, Hoi L, Siebeling RJ & Dalsgaard A (1999) Indolepositive Vibrio vulnificus isolated from disease outbreaks on a Danish eel farm. Dis Aquat Organ 35: 187–194. Deeley MC & Yanofsky C (1981) Nucleotide sequence of the structural gene for tryptophanase of Escherichia coli K-12. J Bacteriol 147: 787–796. Deeley MC & Yanofsky C (1982) Transcription initiation at the tryptophanase promoter of Escherichia coli K-12. J Bacteriol 151: 942–951. DeLisa MP, Valdes JJ & Bentley WE (2001) Mapping stressinduced changes in autoinducer AI-2 production in chemostat-cultivated Escherichia coli K-12. J Bacteriol 183: 2918–2928. DeMoss RD & Moser K (1969) Tryptophanase in diverse bacterial species. J Bacteriol 98: 167–171. Dewhirst FE, Paster BJ, La Fontaine S & Rood JI (1990) Transfer of Kingella indologenes (Snell and Lapage 1976) to the genus Suttonella gen. nov. as Suttonella indologenes comb. nov.; transfer of Bacteroides nodosus (Beveridge 1941) to the genus
2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
440
Dichelobacter gen. nov. as Dichelobacter nodosus comb. nov.; and assignment of the genera Cardiobacterium, Dichelobacter, and Suttonella to Cardiobacteriaceae fam. nov. in the gamma division of Proteobacteria on the basis of 16S rRNA sequence comparisons. Int J Syst Bacteriol 40: 426–433. Diggle SP, Gardner A, West SA & Griffin AS (2007a) Evolutionary theory of bacterial quorum sensing: when is a signal not a signal? Philos T Roy Soc B 362: 1241–1249. Diggle SP, Griffin AS, Campbell GS & West SA (2007b) Cooperation and conflict in quorum-sensing bacterial populations. Nature 450: 411–414. Di Martino P, Fursy R, Bret L, Sundararaju B & Phillips RS (2003) Indole can act as an extracellular signal to regulate biofilm formation of Escherichia coli and other indole-producing bacteria. Can J Microbiol 49: 443–449. Di Martino P, Merieau A, Phillips R, Orange N & Hulen C (2002) Isolation of an Escherichia coli strain mutant unable to form biofilm on polystyrene and to adhere to human pneumocyte cells: involvement of tryptophanase. Can J Microbiol 48: 132–137. Domka J, Lee J & Wood TK (2006) YliH (BssR) and YceP (BssS) regulate Escherichia coli K-12 biofilm formation by influencing cell signaling. Appl Environ Microb 72: 2449–2459. Dong YH, Wang LY & Zhang LH (2007) Quorum-quenching microbial infections: mechanisms and implications. Philos T Roy Soc B 362: 1201–1211. Doukyu N & Aono R (1997) Biodegradation of indole at high concentration by persolvent fermentation with Pseudomonas sp. ST-200. Extremophiles 1: 100–105. Elsden SR, Hilton MG & Waller JM (1976) The end products of the metabolism of aromatic amino acids by Clostridia. Arch Microbiol 107: 283–288. Ensley BD, Ratzkin BJ, Osslund TD, Simon MJ, Wackett LP & Gibson DT (1983) Expression of naphthalene oxidation genes in Escherichia coli results in the biosynthesis of indigo. Science 222: 167–169. Fan S, Meng Q, Saha T, Sarkar FH & Rosen EM (2009) Low concentrations of diindolylmethane, a metabolite of indole-3carbinol, protect against oxidative stress in a BRCA1dependent manner. Cancer Res 69: 6083–6091. Farmer JJ III, Fanning GR, Davis BR et al. (1985) Escherichia fergusonii and Enterobacter taylorae, two new species of Enterobacteriaceae isolated from clinical specimens. J Clin Microbiol 21: 77–81. Fishman A, Tao Y, Rui L & Wood TK (2005) Controlling the regiospecific oxidation of aromatics via active site engineering of toluene para-monooxygenase of Ralstonia pickettii PKO1. J Biol Chem 280: 506–514. Fujisawa T, Shinohara K, Kishimoto Y & Terada A (2006) Effect of miso soup containing Natto on the composition and metabolic activity of the human faecal flora. Microb Ecol Health D 18: 79–84. Fukunaga Y, Kurahashi M, Tanaka K, Yanagi K, Yokota A & Harayama S (2006) Pseudovibrio ascidiaceicola sp. nov.,
2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
J.-H. Lee & J. Lee
isolated from ascidians (sea squirts). Int J Syst Evol Micr 56: 343–347. Fuqua WC, Winans SC & Greenberg EP (1994) Quorum sensing in bacteria: the LuxR–LuxI family of cell density-responsive transcriptional regulators. J Bacteriol 176: 269–275. Gaede HC, Yau WM & Gawrisch K (2005) Electrostatic contributions to indole–lipid interactions. J Phys Chem B 109: 13014–13023. Garbe TR, Kobayashi M & Yukawa H (2000) Indole-inducible proteins in bacteria suggest membrane and oxidant toxicity. Arch Microbiol 173: 78–82. Garcia-Delgado GA, Little PB & Barnum DA (1977) A comparison of various Haemophilus somnus strains. Can J Comp Med 41: 380–388. Gavini F, Mergaert J, Bej A, Mielcarek C, Izard D, Kersters K & De Ley J (1989) Transfer of Enterobacter agglomerans (Beijerinck 1888) Ewing and Fife 1972 to Pantoea gen. nov. as Pantoea agglomerans comb. nov. and description of Pantoea dispersa sp. nov. Int J Syst Bacteriol 39: 337–345. Gerth K, Metzger R & Reichenbach H (1993) Induction of myxospores in Stigmatella aurantiaca (myxobacteria): inducers and inhibitors of myxospore formation, and mutants with a changed sporulation behavior. J Gen Microbiol 139: 865–871. Gilardi GL (1967) Morphological and biochemical characteristics of Aeromonas punctata (hydrophila, liquefaciens) isolated from human sources. Appl Microbiol 15: 417–421. Gillam EM, Notley LM, Cai H, De Voss JJ & Guengerich FP (2000) Oxidation of indole by cytochrome P450 enzymes. Biochemistry 39: 13817–13824. Gong F & Yanofsky C (2002) Analysis of tryptophanase operon expression in vitro: accumulation of TnaC-peptidyl-tRNA in a release factor 2-depleted S-30 extract prevents Rho factor action, simulating induction. J Biol Chem 277: 17095–17100. Gonz´alez Barrios AF, Zuo R, Hashimoto Y, Yang L, Bentley WE & Wood TK (2006) Autoinducer 2 controls biofilm formation in Escherichia coli through a novel motility quorum-sensing regulator (MqsR, B3022). J Bacteriol 188: 305–316. Hammer BK & Bassler BL (2003) Quorum sensing controls biofilm formation in Vibrio cholerae. Mol Microbiol 50: 101–104. Hardie KR & Heurlier K (2008) Establishing bacterial communities by ‘word of mouth’: LuxS and autoinducer 2 in biofilm development. Nat Rev Microbiol 6: 635–643. Hentzer M, Riedel K, Rasmussen TB et al. (2002) Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiology 148: 87–102. Hentzer M, Wu H, Andersen JB et al. (2003) Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J 22: 3803–3815. Higdon JV, Delage B, Williams DE & Dashwood RH (2007) Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res 55: 224–236.
FEMS Microbiol Rev 34 (2010) 426–444
441
Indole signaling in microbial community
Hirakawa H, Inazumi Y, Masaki T, Hirata T & Yamaguchi A (2005) Indole induces the expression of multidrug exporter genes in Escherichia coli. Mol Microbiol 55: 1113–1126. Hirakawa H, Kodama T, Takumi-Kobayashi A, Honda T & Yamaguchi A (2009) Secreted indole serves as a signal for expression of type III secretion system translocators in enterohaemorrhagic Escherichia coli O157:H7. Microbiology 155: 541–550. Hoch JA & Demoss RD (1965) Physiological effects of a constitutive tryptophanase in Bacillus alvei. J Bacteriol 90: 604–610. Holmes B, King A, Phillips I & Lapage SP (1974) Sensitivity of Citrobacter freundii and Citrobacter koseri to cephalosporins and penicillins. J Clin Pathol 27: 729–733. Hooper LV & Gordon JI (2001) Commensal host–bacterial relationships in the gut. Science 292: 1115–1118. Hughes DT & Sperandio V (2008) Inter-kingdom signaling: communication between bacteria and their hosts. Nat Rev Microbiol 6: 111–120. Huys G, Cnockaert M, Janda JM & Swings J (2003) Escherichia albertii sp. nov., a diarrhoeagenic species isolated from stool specimens of Bangladeshi children. Int J Syst Evol Micr 53: 807–810. Ishikado A, Sato T & Mitsuoka T (2007) Suppressive effects of lactulose and magnesium oxide supplementation on fecal putrefactive metabolites with shortening gastrointestinal transit time. Microb Ecol Health D 19: 184–190. Jakab E, Zbinden R, Gubler J, Ruef C, von Graevenitz A & Krause M (1996) Severe infections caused by Propionibacterium acnes: an underestimated pathogen in late postoperative infections. Yale J Biol Med 69: 477–482. Jansson DS, Johansson KE, Olofsson T et al. (2004) Brachyspira hyodysenteriae and other strongly b-haemolytic and indolepositive spirochaetes isolated from mallards (Anas platyrhynchos). J Med Microbiol 53: 293–300. Jayaraman A & Wood TK (2008) Bacterial quorum sensing: signals, circuits, and implications for biofilms and disease. Annu Rev Biomed Eng 10: 145–167. John F & Wyeth S (1919) The effects of acids, alkalies, and sugars on the growth and indole formation of Bacillus coli. Biochem J 13: 10–24. Kamath AV & Vaidyanathan CS (1990) New pathway for the biodegradation of indole in Aspergillus niger. Appl Environ Microb 56: 275–280. Kawamura-Sato K, Shibayama K, Horii T, Iimuma Y, Arakawa Y & Ohta M (1999) Role of multiple efflux pumps in Escherichia coli in indole expulsion. FEMS Microbiol Lett 179: 345–352. Keller L & Surette MG (2006) Communication in bacteria: an ecological and evolutionary perspective. Nat Rev Microbiol 4: 249–258. Kilian M (1976) A taxonomic study of the genus Haemophilus, with the proposal of a new species. J Gen Microbiol 93: 9–62. Kobayashi A, Hirakawa H, Hirata T, Nishino K & Yamaguchi A (2006) Growth phase-dependent expression of drug exporters
FEMS Microbiol Rev 34 (2010) 426–444
in Escherichia coli and its contribution to drug tolerance. J Bacteriol 188: 5693–5703. Kwon YM & Weiss B (2009) Production of 3-nitrosoindole derivatives by Escherichia coli during anaerobic growth. J Bacteriol 191: 5369–5376. Lambert C, Nicolas JL, Cilia V & Corre S (1998) Vibrio pectenicida sp. nov., a pathogen of scallop (Pecten maximus) larvae. Int J Syst Bacteriol 48 (Part 2): 481–487. Langworth BF (1977) Fusobacterium necrophorum: its characteristics and role as an animal pathogen. Bacteriol Rev 41: 373–390. Laurie AD & Lloyd-Jones G (1999) The phn genes of Burkholderia sp. strain RP007 constitute a divergent gene cluster for polycyclic aromatic hydrocarbon catabolism. J Bacteriol 181: 531–540. Lecadet MM, Frachon E, Dumanoir VC, Ripouteau H, Hamon S, Laurent P & Thiery I (1999) Updating the H-antigen classification of Bacillus thuringiensis. J Appl Microbiol 86: 660–672. Lee J, Bansal T, Jayaraman A, Bentley WE & Wood TK (2007a) Enterohemorrhagic Escherichia coli biofilms are inhibited by 7-hydroxyindole and stimulated by isatin. Appl Environ Microb 73: 4100–4109. Lee J, Jayaraman A & Wood TK (2007b) Indole is an inter-species biofilm signal mediated by SdiA. BMC Microbiol 7: 42. Lee J, Page R, Garc´ıa-Contreras R et al. (2007c) Structure and function of the Escherichia coli protein YmgB: a protein critical for biofilm formation and acid-resistance. J Mol Biol 373: 11–26. Lee J, Zhang XS, Hegde M, Bentley WE, Jayaraman A & Wood TK (2008) Indole cell signaling occurs primarily at low temperatures in Escherichia coli. ISME J 2: 1007–1023. Lee J, Attila C, Cirillo SLG, Cirillo JD & Wood TK (2009a) Indole and 7-hydroxyindole diminish Pseudomonas aeruginosa virulence. Microb Biotechnol 2: 75–90. Lee J, Maeda T, Hong SH & Wood TK (2009b) Reconfiguring the quorum-sensing regulator SdiA of Escherichia coli to control biofilm formation via indole and N-acylhomoserine lactones. Appl Environ Microb 75: 1703–1716. Lesic B, L´epine F, D´eziel E et al. (2007) Inhibitors of pathogen intercellular signals as selective anti-infective compounds. PLoS Pathog 3: 1229–1239. Li Y, Cole K & Altman S (2003) The effect of a single, temperature-sensitive mutation on global gene expression in Escherichia coli. RNA 9: 518–532. Liu Y, Mee BJ & Mulgrave L (1997) Identification of clinical isolates of indole-positive Klebsiella spp., including Klebsiella planticola, and a genetic and molecular analysis of their blactamases. J Clin Microbiol 35: 2365–2369. Martin K, Morlin G, Smith A, Nordyke A, Eisenstark A & Golomb M (1998) The tryptophanase gene cluster of Haemophilus influenzae type b: evidence for horizontal gene transfer. J Bacteriol 180: 107–118. Mathesius U, Charon C, Rolfe BG, Kondorosi A & Crespi M (2000) Temporal and spatial order of events during the
2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
442
induction of cortical cell divisions in white clover by Rhizobium leguminosarum bv. trifolii inoculation or localized cytokinin addition. Mol Plant Microbe In 13: 617–628. Merhej V, Adekambi T, Pagnier I, Raoult D & Drancourt M (2008) Yersinia massiliensis sp. nov., isolated from fresh water. Int J Syst Evol Micr 58: 779–784. Moncla BJ, Braham P, Rabe LK & Hillier SL (1991) Rapid presumptive identification of black-pigmented gram-negative anaerobic bacteria by using 4-methylumbelliferone derivatives. J Clin Microbiol 29: 1955–1958. Monds RD & O’Toole GA (2008) Metabolites as intercellular signals for regulation of community-level traits. Chemical Communication Among Bacteria (Winans SC & Bassler BL, eds), pp. 105–130. ASM Press, Washington, DC. Montalvo-Rodriguez R, Vreeland RH, Oren A, Kessel M, Betancourt C & Lopez-Garriga J (1998) Halogeometricum borinquense gen. nov., sp. nov., a novel halophilic archaeon from Puerto Rico. Int J Syst Bacteriol 48 (Part 4): 1305–1312. Moore RL (1981) The biology of Hyphomicrobium and other prosthecate, budding bacteria. Annu Rev Microbiol 35: 567–594. Mueller RS, McDougald D, Cusumano D, Sodhi N, Kjelleberg S, Azam F & Bartlett DH (2007) Vibrio cholerae strains possess multiple strategies for abiotic and biotic surface colonization. J Bacteriol 189: 5348–5360. Mueller RS, Beyhan S, Saini SG, Yildiz FH & Bartlett DH (2009) Indole acts as an extracellular cue regulating gene expression in Vibrio cholerae. J Bacteriol. Nadell CD, Xavier JB, Levin SA & Foster KR (2008) The evolution of quorum sensing in bacterial biofilms. PLoS Biol 6: e14. Neiditch MB, Federle MJ, Miller ST, Bassler BL & Hughson FM (2005) Regulation of LuxPQ receptor activity by the quorumsensing signal autoinducer-2. Mol Cell 18: 507–518. Neish AS (2009) Microbes in gastrointestinal health and disease. Gastroenterology 136: 65–80. Newton WA & Snell EE (1965) Formation and interrelationships of tryptophanase and tryptophan synthetases in Escherichia coli. J Bacteriol 89: 355–364. Nicolaus B, Lama L, Esposito E et al. (1999) Haloarcula spp. able to biosynthesize exo- and endopolymers. J Ind Microbiol Biot 23: 489–496. Nikaido E, Yamaguchi A & Nishino K (2008) AcrAB multidrug efflux pump regulation in Salmonella enterica serovar Typhimurium by RamA in response to environmental signals. J Biol Chem 283: 24245–24253. Nishida S & Nakagawara G (1964) Isolation of toxigenic strains of Clostridium novyi from soil. J Bacteriol 88: 1636–1640. Nishino K, Honda T & Yamaguchi A (2005) Genome-wide analyses of Escherichia coli gene expression responsive to the BaeSR two-component regulatory system. J Bacteriol 187: 1763–1772. O’Hara CM, Brenner FW & Miller JM (2000) Classification, identification, and clinical significance of Proteus, Providencia, and Morganella. Clin Microbiol Rev 13: 534–546.
2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
J.-H. Lee & J. Lee
Ohno M, Shiratori H, Park MJ et al. (2000) Symbiobacterium thermophilum gen. nov., sp. nov., a symbiotic thermophile that depends on co-culture with a Bacillus strain for growth. Int J Syst Evol Micr 50 (Part 5): 1829–1832. Patankar AV & Gonzalez JE (2009) Orphan LuxR regulators of quorum sensing. FEMS Microbiol Rev 33: 739–756. Pavan ME, Abbott SL, Zorzopulos J & Janda JM (2000) Aeromonas salmonicida subsp. pectinolytica subsp. nov., a new pectinase-positive subspecies isolated from a heavily polluted river. Int J Syst Evol Micr 50 (Part 3): 1119–1124. Peel MM, Alfredson DA, Gerrard JG et al. (1999) Isolation, identification, and molecular characterization of strains of Photorhabdus luminescens from infected humans in Australia. J Clin Microbiol 37: 3647–3653. Pickett MJ (1989) Methods for identification of flavobacteria. J Clin Microbiol 27: 2309–2315. Pittard AJ (1996) Biosynthesis of the aromatic amino acids: the tryptophan pathway. Escherichia coli and Salmonella: Cellular and Molecular Biology (Neidhardt FC, ed), pp. 458–484. ASM Press, Washington, DC. Postgate JR & Campbell LL (1966) Classification of Desulfovibrio species, the nonsporulating sulfate-reducing bacteria. Bacteriol Rev 30: 732–738. Raffa RG & Raivio TL (2002) A third envelope stress signal transduction pathway in Escherichia coli. Mol Microbiol 45: 1599–1611. Rasmussen TB & Givskov M (2006) Quorum-sensing inhibitors as anti-pathogenic drugs. Int J Med Microbiol 296: 149–161. Ren D, Bedzyk LA, Ye RW, Thomas SM & Wood TK (2004) Differential gene expression shows natural brominated furanones interfere with the autoinducer-2 bacterial signaling system of Escherichia coli. Biotechnol Bioeng 88: 630–642. Rezwan F, Lan R & Reeves PR (2004) Molecular basis of the indole-negative reaction in Shigella strains: extensive damages to the tna operon by insertion sequences. J Bacteriol 186: 7460–7465. Rickard AH, Palmer RJ Jr, Blehert DS et al. (2006) Autoinducer 2: a concentration-dependent signal for mutualistic bacterial biofilm growth. Mol Microbiol 60: 1446–1456. Riveros R, Haun M & Duran N (1989) Effect of growth conditions on production of violacein by Chromobacterium violaceum (BB-78 strain). Braz J Med Biol Res 22: 569–577. Robertson GT, Doyle TB, Du Q, Duncan L, Mdluli KE & Lynch AS (2007) A novel indole compound that inhibits Pseudomonas aeruginosa growth by targeting MreB is a substrate for MexAB-OprM. J Bacteriol 189: 6870–6881. Rui L, Kwon YM, Fishman A, Reardon KF & Wood TK (2004) Saturation mutagenesis of toluene ortho-monooxygenase of Burkholderia cepacia G4 for enhanced 1-naphthol synthesis and chloroform degradation. Appl Environ Microb 70: 3246–3252. Rui L, Reardon KF & Wood TK (2005) Protein engineering of toluene ortho-monooxygenase of Burkholderia cepacia G4 for regiospecific hydroxylation of indole to form various indigoid compounds. Appl Microbiol Biot 66: 422–429.
FEMS Microbiol Rev 34 (2010) 426–444
443
Indole signaling in microbial community
Ryan RP & Dow JM (2008) Diffusible signals and interspecies communication in bacteria. Microbiology 154: 1845–1858. Sakazaki R (1968) Proposal of Vibrio alginolyticus for the biotype 2 of Vibrio parahaemolyticus. Jpn J Med Sci Biol 21: 359–362. Sakazaki R, Iwanami S & Fukumi H (1963) Studies on the enteropathogenic, facultatively halophilic bacteria, Vibrio parahaemolyticus. I. Morphological, cultural and biochemical properties and its taxonomical position. Jpn J Med Sci Biol 16: 161–188. Schindler PR (1984) Isolation of Yersinia enterocolitica from drinking water in South Bavaria. Zbl Bakt Mik Hyg B 180: 76–84. Schleifer KH, Kilpper-Balz R, Kraus J & Gehring F (1984) Relatedness and classification of Streptococcus mutans and ‘mutans-like’ streptococci. J Dent Res 63: 1047–1050. Schuster M, Lostroh CP, Ogi T & Greenberg EP (2003) Identification, timing, and signal specificity of Pseudomonas aeruginosa quorum-controlled genes: a transcriptome analysis. J Bacteriol 185: 2066–2079. Schuurmans DM, Olson BH & San Clemente CL (1956) Production and isolation of thermoviridin, an antibiotic produced by Thermoactinomyces viridis n. sp. Appl Microbiol 4: 61–66. Sedlak J, Puchmayerova-Slajsova M, Keleti J & Luderitz O (1971) On the taxonomy, ecology and immunochemistry of genus Citrobacter. J Hyg Epid Microb Im 15: 366–374. Shiner EK, Rumbaugh KP & Williams SC (2005) Interkingdom signaling: deciphering the language of acyl homoserine lactones. FEMS Microbiol Rev 29: 935–947. Simmons DJ & Simpson W (1977) The biochemical and cultural characteristics of Pasteurella pneumotropica. Med Lab Sci 34: 145–148. Smith PB, Rhoden DL, Tomfohrde KM, Dunn CR, Balows A & Hermann GJ (1971) R-B enteric differential system for identification of Enterobacteriaceae. Appl Microbiol 21: 1036–1039. Smith T (1897) A modification of the method for determining the production of indol by bacteria. J Exp Med 2: 543–547. Snell EE (1975) Tryptophanase: structure, catalytic activities, and mechanism of action. Adv Enzymol RAMB 42: 287–333. Socransky SS, Listgarten M, Hubersak C, Cotmore J & Clark A (1969) Morphological and biochemical differentiation of three types of small oral spirochetes. J Bacteriol 98: 878–882. Stamm I, Lottspeich F & Plaga W (2005) The pyruvate kinase of Stigmatella aurantiaca is an indole binding protein and essential for development. Mol Microbiol 56: 1386–1395. Stull TL, Hyun L, Sharetzsky C, Wooten J, McCauley JP Jr & Smith AB III (1995) Production and oxidation of indole by Haemophilus influenzae. J Biol Chem 270: 5–8. Sulakvelidze A (2000) Yersiniae other than Y. enterocolitica, Y. pseudotuberculosis, and Y. pestis: the ignored species. Microbes Infect 2: 497–513. Surette MG & Bassler BL (1998) Quorum sensing in Escherichia coli and Salmonella typhimurium. P Natl Acad Sci USA 95: 7046–7050.
FEMS Microbiol Rev 34 (2010) 426–444
Surette MG & Bassler BL (1999) Regulation of autoinducer production in Salmonella typhimurium. Mol Microbiol 31: 585–595. Tannock GW (1977) Characteristics of Bacteroides isolates from the cecum of conventional mice. Appl Environ Microb 33: 745–750. Tao Y, Fishman A, Bentley WE & Wood TK (2004) Altering toluene 4-monooxygenase by active-site engineering for the synthesis of 3-methoxycatechol, methoxyhydroquinone, and methylhydroquinone. J Bacteriol 186: 4705–4713. Tewari YB & Goldberg RN (1994) An equilibrium and calorimetric investigation of the hydrolysis of L-tryptophan to (indole1pyruvate1ammonia). J Solution Chem 23: 167–184. Tison DL, Nishibuchi M, Greenwood JD & Seidler RJ (1982) Vibrio vulnificus biogroup 2: new biogroup pathogenic for eels. Appl Environ Microb 44: 640–646. Vancanneyt M, Nedashkovskaya OI, Snauwaert C et al. (2006) Larkinella insperata gen. nov., sp. nov., a bacterium of the phylum ‘Bacteroidetes’ isolated from water of a steam generator. Int J Syst Evol Micr 56: 237–241. Vendeville A, Winzer K, Heurlier K, Tang CM & Hardie KR (2005) Making ‘sense’ of metabolism: autoinducer-2, LuxS and pathogenic bacteria. Nat Rev Microbiol 3: 383–396. von Graevenitz A (1971) Practical substitution for the indol, methyl red, Voges-Proskauer, citrate system. Appl Microbiol 21: 1107–1109. Wang D, Ding X & Rather PN (2001) Indole can act as an extracellular signal in Escherichia coli. J Bacteriol 183: 4210–4216. Waters CM & Bassler BL (2005) Quorum sensing: cell-to-cell communication in bacteria. Annu Rev Cell Dev Bi 21: 319–346. Waters CM & Bassler BL (2006) The Vibrio harveyi quorumsensing system uses shared regulatory components to discriminate between multiple autoinducers. Gene Dev 20: 2754–2767. Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC & Siuzdak G (2009) Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. P Natl Acad Sci USA 106: 3698–3703. Williams P & C´amara M (2009) Quorum sensing and environmental adaptation in Pseudomonas aeruginosa: a tale of regulatory networks and multifunctional signal molecules. Curr Opin Microbiol 12: 182–191. Williams P, Winzer K, Chan WC & C´amara M (2007) Look who’s talking: communication and quorum sensing in the bacterial world. Philos T Roy Soc B 362: 1119–1134. Winzer K, Hardie KR & Williams P (2002) Bacterial cell-to-cell communication: sorry, can’t talk now – gone to lunch! Curr Opin Microbiol 5: 216–222. Xavier KB & Bassler BL (2003) LuxS quorum sensing: more than just a numbers game. Curr Opin Microbiol 6: 191–197. Xavier KB & Bassler BL (2005a) Regulation of uptake and processing of the quorum-sensing autoinducer AI-2 in Escherichia coli. J Bacteriol 187: 238–248.
2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
444
Xavier KB & Bassler BL (2005b) Interference with AI-2-mediated bacterial cell-cell communication. Nature 437: 750–753. Yamaguchi S & Yokoe M (2000) A novel protein-deamidating enzyme from Chryseobacterium proteolyticum sp. nov., a newly isolated bacterium from soil. Appl Environ Microb 66: 3337–3343. Yanofsky C, Horn V & Gollnick P (1991) Physiological studies of tryptophan transport and tryptophanase operon induction in Escherichia coli. J Bacteriol 173: 6009–6017. Yao Y, Martinez-Yamout MA, Dickerson TJ, Brogan AP, Wright PE & Dyson HJ (2006) Structure of the Escherichia coli quorum sensing protein SdiA: activation of the folding switch by acyl homoserine lactones. J Mol Biol 355: 262–273.
2010 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved
c
J.-H. Lee & J. Lee
Yin B, Gu J-D & Wan N (2005) Degradation of indole by enrichment culture and Pseudomonas aeruginosa Gs isolated from mangrove sediment. Int Biodeter Biodegr 56: 243–248. Zhang LH & Dong YH (2004) Quorum sensing and signal interference: diverse implications. Mol Microbiol 53: 1563–1571. Zhang XS, Garc´ıa-Contreras R & Wood TK (2007) YcfR (BhsA) influences Escherichia coli biofilm formation through stress response and surface hydrophobicity. J Bacteriol 189: 3051–3062. Zhao JS, Manno D, Beaulieu C, Paquet L & Hawari J (2005) Shewanella sediminis sp. nov., a novel Na1-requiring and hexahydro-1,3,5-trinitro-1,3,5-triazine-degrading bacterium from marine sediment. Int J Syst Evol Micr 55: 1511–1520.
FEMS Microbiol Rev 34 (2010) 426–444